The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20

被引:232
|
作者
Shembade, Noula [1 ]
Harhaj, Nicole S. [1 ]
Parvatiyar, Kislay [1 ]
Copeland, Neal G. [2 ]
Jenkins, Nancy A. [2 ]
Matesic, Lydia E. [2 ,3 ]
Harhaj, Edward W. [1 ]
机构
[1] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Microbiol & Immunol, Miami, FL 33136 USA
[2] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA
[3] Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA
关键词
D O I
10.1038/ni1563
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-kappa B; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule TAX1BP1 recruited the E3 ligase Itch to A20 via two 'PPXY' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling A20-mediated recruitment and inactivation of RIP1. Furthermore, the Tax oncoprotein of human T cell leukemia virus type I targeted this complex for inactivation by disrupting the interaction among TAX1BP1, A20 and Itch. Thus, our studies show a previously unappreciated complexity of A20 substrate recognition and inactivation whereby TAX1BP1 and Itch function as essential subunits of an A20 ubiquitin-editing complex.
引用
收藏
页码:254 / 262
页数:9
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